While iron is critical for normal cellular processes, excess iron causes cellular damage. Maintenance of iron balance is therefore crucial to avoid the morbidity and mortality associated with iron deficiency and iron overload. Hepcidin, a small, circulating peptide produced by the liver, is a key regulator of iron homeostasis that decreases intestinal iron absorption. In congenital iron loading anemias and in forms of hereditary hemochromatosis, hepcidin levels are inappropriately low, allowing absorption of dietary iron to persist despite increased total body iron stores. TMPRSS6, a transmembrane serine protease produced by the liver, acts as an essential negative regulator of hepcidin expression in humans and mice, through a mechanism that has yet to be elucidated. Given that iron metabolism is very similar among mammalian species, the central hypothesis of this application is that genes that regulate iron stores in mice also modify the clinical expression of human disorders of iron homeostasis. This proposal aims to: 1) Determine whether loss of Tmprss6 function modifies iron loading in murine models of juvenile hemochromatosis, HFE-hemochromatosis, and beta-thalassemia intermedia;and 2) Identify novel genes that, when mutated, modulate iron homeostasis in mice. Future work will focus on characterizing the normal function of these novel murine genes and whether the human orthologues of these genes function as phenotypic modifiers in known iron disorders. The rationale for the proposed research is that improved understanding of the molecular mechanisms that control systemic iron homeostasis may improve therapeutic outcomes for patients with disorders of iron metabolism. This project, conducted under the guidance of Dr. Nancy Andrews, will provide the Candidate with a period of mentored research during which she will develop an independent research program. This project is designed to provide training in iron biology and mouse genetics that will enable the Candidate to develop an academic career in clinical and molecular pathology with a focus on the molecular genetics of disorders of iron homeostasis in mice and humans. PUBLIC HEALH RELEVANCE: Iron deficiency and iron excess are both detrimental to human health. This research aims to identify and characterize genes that are important in controlling the amount of iron stored in the body. It is hoped that this work will lead to new treatments for both inherited and acquired iron disorders and to the development of new clinical tests that can predict prognosis and guide therapy in these disorders.